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Roßmann and colleagues report a simple strategy to generate a panel of fluorescent HaloTag Ligands that enable visualisation of cell surface proteins at low concentrations and with brief incubation times. They use these probes to label neuromodulatory receptors in neurons, allowing for the distinction of surface versus internal receptors of the presynaptic terminal.

JMML is an aggressive hematologic malignancy with myeloproliferative characteristics affecting young children. Here the authors report that C-type lectin-like molecule-1 (CLL-1) is upregulated in JMML and they develop CLL-1 CAR T cells showing in vitro and in vivo anti-JMML activity.

Kaposi’s sarcoma-associated herpesvirus changes mitochondrial architecture via vBcl-2 interaction with a host NDP kinase, which triggers mitochondrial fission and inhibition of MAVS allowing for virus production.

Here the authors reveal how replication stress in BRCA2-deficient cells triggers a mutagenic cycle of APOBEC3B upregulation, uracil accumulation at stalled forks, and DNA damage, uncovering a self-reinforcing loop that fuels genomic instability.

Ketogenesis is critical for survival during the neonatal and perinatal periods. Arima et al. determine that hepatic ketogenesis prevents hyperacetylation of mitochondrial proteins and disruption of mitochondrial energetics.

The role of outer mitochondrial membrane proteins in Myocardial Ischemia-reperfusion Injury (MIRI) largely remains unknown. Here, the authors demonstrate that the outer mitochondrial membrane protein Myocardial Mitochondrial Antiviral Signaling (MAVS) protein promotes MIRI suggesting MAVS protein as potential therapeutic target.

It has been suggested that targeting the PD-1/PD-L1 axis can increase the anti-tumor properties of chimeric antigen receptor (CAR)-T cells. Here the authors report that CAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition.

Metaphase chromosomes oscillate while attached to growing and shrinking microtubules. Here, the authors show that an α-tubulin detyrosination gradient on kinetochore microtubules fine-tunes load-bearing attachments during chromosome oscillations.

DNA methylation is a repressive modification that is essential for development. Here the authors reveal a critical role for DNA methylation in placental development during pregnancy. Failure to properly establish placental DNA methylation patterns compromises not only placental function, but embryo survival.

Transcriptomic and proteomic analyses show that high levels of the extracellular-matrix protein osteopontin are associated with the attenuated foreign-body response elicited by breast silicone implants wrapped with acellular dermal matrix.

In neurons, the microtubule cytoskeleton provides support and directionality of axons. Here, the authors report that microtubule dynamics in axons may be regulated by the autophagy proteins (ATGs) independently of their known role in autophagy.

Tumor loss of IFN-γ signalling is a major mechanism of resistance to immune checkpoint blockers. Here the authors report that melanoma cells with knockout of IFNγR1 show constitutive JAK1/2 activation and that the JAK1/2 inhibitor ruxolitinib can overcome resistance to anti-CTLA-4 therapy.

Immunotherapy has yet to demonstrate efficacy for patients with glioblastoma. Here, the authors employ human single-cell RNA-seq, spatial transcriptomics, and a preclinical mouse model to show that glioblastoma cell-derived synaptogenic factor Thrombospondin-1 promotes neuronal circuit remodeling and regional immunosuppression, highlighting a potential therapeutic target.

We conducted a CRISPR screen to identify genes essential for neural differentiation. By integrating these findings with mouse neuroanatomy, we demonstrated its utility in discovering a new PEDS1-related neurodevelopmental disorder.

Beta3-adrenergic receptor signaling regulates adipose tissue browning. Here, the authors show that barr2 regulates internalization of beta3-adrenergic receptors and that mice lacking barr2 in adipocytes are protected from diet-induced weight gain and metabolic complications.

Adipose tissue-resident T cells are known to regulate thermogenesis and energy expenditure. Here the authors report that deletion of mitochondria-localized protein DsbA-L in T cells promotes diet-induced thermogenesis via suppressing IFN-γ production.

The MCM8/9 helicase has been implicated in DNA recombination processes with mutations in these genes causative for infertility and cancer. Here, the authors show that MCM8/9 aids normal fork progression and also stabilizes persistently stalled forks, acting upstream of RAD51 and BRCA1.

The IRE1α-XBP1s pathway has been implicated in the regulation of anti-tumor immunity. Here the authors show that IRE1α is increased in prostate cancer (PCa) and that its inhibition reprograms the tumor microenvironment, promoting anti-tumor immune responses in PCa preclinical models.

The production of hematopoietic stem cells in the embryo is precisely regulated by various intrinsic and extrinsic factors. Here, the authors find that autophagy is involved in the maturation of hematopoietic precursors through nucleolin pathways.

We find that PTP1B and ABL1/2 reciprocally control RNF213 tyrosine phosphorylation and its oligomerization and RZ domain activation, and identify a unique PTP1B–RNF213–CYLD–SPATA2 pathway critical for the control of inflammatory cell death in hypoxic tumours.

Tumor pericytes are located surrounding blood vessels, and can regulate tumor vascular structure. Here, the authors discover that a subpopulation of NKX2-3 high tumor pericytes modulates vasodilation and hemodynamics to promote metastasis.

The internalization of GPCRs is a key process that regulates their intracellular signaling. Here, the authors reveal the importance of β-arrestins in the internalization of 60 GPCRs and identify the β-arrestin-independent and -dependent mechanisms for GLP-1R internalization.

Polycomb repressive complex 2 (PRC2) methylates H3K27 and suppresses RNA polymerase II transcription by promoting a closed chromatin. Here the authors identify the transcription factor Ybx1 as an interactor that regulates the binding of PRC2 to chromatin and H3K27 methylation to promote the genetic programs underlying neural lineages and neural progenitor self-renewal–differentiation choices.

The authors add to our knowledge of the transcriptional regulation of the meiotic program in mice spermatocytes, showing ZFP541 regulates meiotic prophase and transition to the division phase by being the target for upstream factors MEIOSIN/STRA8.

Identifying how genetic alterations cooperate in cancer is challenging. Here the authors analyze leukemia mouse models with both oncogenic NRAS and EZH2 mutations using single-cell RNA-sequencing, evaluate oncogenic cooperation, and identify GEM as a regulator of leukemia-initiating cells.

ATRX is a chromatin remodeling protein, which loss has been associated to replication stress, DNA damage, and DNA repair failures that drive genome instability. Here the authors reveal that ATRX protects genomic integrity at G4-containing regions by maintaining these regions in a closed heterochromatic state.

This protocol combines pooled CRISPR–Cas9 screening with neural organoid and assembloid models and illustrates how it can be applied to map hundreds of disease genes onto cellular pathways and specific aspects of human neural development.

Despite the importance of osteoclast secretory lysosomes in bone digestion, the proteins that regulate them remain ill defined. Here, the authors identify Slc37a2 as a secretory lysosome sugar transporter that is required for maintenance of skeletal bone mass.

Calorie burning is normally turned off in thermogenic brown fat at warm temperatures. Here the authors show that adipocyte oxygen sensing directly boosts brown fat calorie burning, even at warm temperatures.

Gut microbiota deficient mice demonstrate enhanced glucose clearance, but which tissues are responsible for this improvement are still unclear. Here the authors report that brown adipose tissue contributes to the enhanced glucose clearance in gut microbiota depleted mice and that this response is dissociated from adaptive thermogenesis.

Parkinson’s disease (PD) features visual dysfunction. Here the authors show mice lacking VPS35, a retromer component genetically linked to PD, in rods have impaired vision, retinal degradation and a-synuclein inclusions.

The polarity separation within the carbon-metal bonds of traditional organometallic reagents that endows them with exceptional reactivities also imposes limitations, such as air and moisture sensitivity, and flammability. Here, the authors demonstrate that stable and easily accessible benzylic (or allylic) boronate with mild alkali-metal alkoxide as the activator can act as organometallic reagents.

The anti-CD38 monoclonal antibody Daratumumab is approved for the treatment of multiple myeloma but efficiency is curtailed by secondary resistance. Here authors show that the antibody-dependent cellular cytotoxicity, which is the main mechanism of action for Daratumumab, is regulated by KDM6A via Histone H3 K27 methylation of CD38 and CD48, downregulation of which leads to drug resistance.

We find that, in mice, although the individual loss of Parkin or OMA1 does not affect mitochondrial integrity, their combined loss results in small body size, low locomotor activity, premature death, mitochondrial abnormalities and innate immune responses.

Marin et al. report the role of lamin proteins and the lamin B receptor (LBR) in chromatin positioning at the nuclear periphery. Knockout of all lamins and LBR in mouse embryonic stem cells leads to heterochromatin detachment and derepression of gene and transposon expression.

The efficacy of T-cell-based cancer immunotherapies can be compromised by T cell exhaustion. Here the authors develop a human ex vivo exhaustion model and, based on a CRISPR-Cas9 screen, identify SNX9 as a regulator of T cell exhaustion, showing that SNX9 knockout is associated with improved T cell function and anti-tumor activity in preclinical cancer models.

Hop, also known as Stip1 or Sti1, facilitates substrate transfer between the Hsp70 and Hsp90 molecular chaperones. Characterization of proteostasis-related pathways in STIP1 knock-out cell lines reveals that in eukaryotes Stip1 modulates the balance between protein folding and degradation.

Response to PD-1 checkpoint blockade is unpredictable in lung cancer patients. Here authors show in human lung and mouse tumour models that low or absent α_V integrin expression leads to better tumour growth control by anti-PD-1 via reduced TGF-β activation and hence increased infiltration of anti-tumour CD8⁺ T cells.

Hong, Li and colleagues unveil a pivotal role of TET2 in heterochromatin relocalization, aberrant upregulation of endogenous retroviruses and overactivated innate immune response in hematopoietic stem and progenitor cells during aging.

The balance of stem cell maintenance, differentiation, and programmed death is critical for proper development. Here they show that SNIP1 is critical for stem cell survival and differentiation in the developing brain where it acts downstream of TGFb and NFkB and regulates PRC2 activities for governing cell fates.

A survey of the reconstructed gene set of the last eukaryotic common ancestor shows a consistent link between Asgard archaea and the origin of numerous, functionally diverse eukaryotic genes, demonstrating the dominant Asgard contribution to eukaryogenesis.

Genetic alteration can render tumor cells resistant to immune cell-mediated killing. Here based on a genome-wide CRISPR screening, the authors show that expression of CHMP2A confers tumor cell resistance to NK cell-mediated cytotoxicity, mechanistically involving CHMP2A-dependent regulation of extracellular vesicle secretion.

Protein kinase R (PKR) has been suggested to act as a mediator of ER stress and inflammation in obesity. Here, Lancaster et al. find that genetic loss of PKR does not alter the development of obesity, and suggest that the use of littermate controls may explain differences in mouse knockout phenotypes.

USP30 has been proposed to regulate mitophagy, a relevant Parkinson’s disease mechanism. Here, the authors show that Usp30 knockout mice and USP30 inhibitors like MTX115325 demonstrate neuroprotective responses in an alpha-synuclein mouse model of Parkinson’s disease.

Fc–Fc gamma receptor interactions and alveolar macrophages contribute to ancestral vaccine-induced control of infection with SARS-CoV-2 variants in mice.

Here, the authors show that there is a pretumorigenic T_H17 subset in the intestines that can convert to being tumorigenic under the control of KLF6 and that this process can be prevented by TGFβ1 production from intestinal epithelial cells.

Li et al. discovered that the cytotoxic synthetic small molecule BRD1732 is directly ubiquitinated in cells. Ubiquitination of BRD1732 is E3 ligase dependent and leads to inhibition of proteasomal degradation.

The ability of bone marrow to recruit transplanted hematopoietic stem cells decreases with age. Here, the authors demonstrate that this decline is caused by reduced sinusoidal shear stress due to increased non-neuronal acetylcholine degradation.

Here, Santamaria de Souza et al. explore the context-dependent fitness effects of glpT-deficiency in Salmonella enterica, showing mutants thrive in the gut lumen but are counter-selected by macrophages, highlighting antagonistic pleiotropy and niche-dependent adaptation.